rs1045642

A meta-analysis of 32 studies (21,692 individuals) examined SNPs associated with statin-induced myopathy (SIM). SLCO1B1 rs4149056 C allele significantly increased SIM risk in heterozygous (OR ~1.58), homozygous (OR ~4.47), dominant (OR ~1.89), and recessive (OR ~4.54) models. SLCO1B1 rs4363657 C allele was protective, and GATM rs9806699 A allele carriers had lower SIM risk with rosuvastatin treatment.

This pilot study investigated associations between genetic polymorphisms in transporter genes (SLC19A1, ABCC2, ABCB1, ABCC1, ABCC3, ABCG2) and clinical response to methotrexate (MTX) in 100 Chinese rheumatoid arthritis (RA) patients. Multiple SNPs showed significant associations with MTX response: SLC19A1 rs12659 and rs3788200 major alleles were associated with EULAR good/moderate response (RR=1.42-1.45, p=0.03-0.04); ABCC2 rs3740066 major allele was associated with DAS28-ESR low disease activity (RR=0.67, p=0.02). Haplotype analysis identified significant associations of SLC19A1 and ABCC2 haplotypes with clinical response outcomes.

A prospective study of 91 primary central nervous system lymphoma (PCNSL) patients examined genetic polymorphisms in DNA repair, one-carbon metabolism, and metabolism genes as prognostic markers. ABCB1 rs1045642 was identified as an independent prognostic factor, with the CC genotype significantly associated with shorter progression-free survival (PFS: 16 months CC vs. 27 months TT/CT, HR=1.9, P=0.036) and higher risk of disease progression compared to T allele carriers.

This PhD thesis comprises multiple studies examining personalized treatment with psychiatric drugs through pharmacogenetics and therapeutic drug monitoring. Two key studies examined: (1) ABCB1 polymorphisms (rs1045642, rs2032582, rs4148739, rs2235040, rs2235015, rs2032583, rs28401781, rs9282564) in relation to antidepressant response in 152 Russian patients with moderate-to-severe depression over 4 weeks, finding rs2235040 and rs4148739 influenced timing of antidepressant response (early vs late). (2) ABCB1 polymorphisms and antipsychotic-induced hyperprolactinemia in Russian schizophrenia patients (N=186), revealing rs2032582 (G2677T) was protective against hyperprolactinemia in the risperidone/paliperidone subgroup. (3) CYP17 polymorphism (rs743572, T34C) and tardive dyskinesia in 146 patients, finding CYP17 CC genotype protective against tardive dyskinesia, though not mediated through DHEA(S) levels.

This dissertation examined pharmacogenetic associations with clozapine adverse effects in 237 Finnish schizophrenia patients. ADRA2A rs1800544 was associated with clozapine-induced sialorrhea (OR 2.13, 95% CI: 1.17-3.88, p=0.013). Eight HNMT SNPs in complete linkage disequilibrium (r²=1) were associated with sedation. CHRM3 rs685548 and weighted genetic risk scores from HTR4, HTR7, TPH1, CHRM2, ABCB1, and OPRM1 were associated with anticholinergic symptoms.

Case-control study of 1,000 Han Chinese individuals (450 epilepsy cases, 550 controls) examining associations between STX1B polymorphisms and epilepsy treatment response. The rs140820592 variant showed significant association with reduced epilepsy risk (OR=0.542, p=0.004) and drug-resistant epilepsy risk (OR=0.260, p=0.004), with eQTL analysis confirming rs140820592 regulates STX1B expression in brain tissues.

A Russian-language review examining molecular and genetic aspects of cardiotoxicity from anticancer chemotherapy. The paper discusses genetic polymorphisms in ABC transporters (ABCC1, ABCC2, ABCB1), nucleotide transporters (SLC28A3), and genes involved in oxidative stress (CYBA, RAC2, NCF4, CBR3) that predispose patients to chemotherapy-induced cardiotoxicity. Key findings include rs8187710 in ABCC2 (p=0.0009), rs4673 in CYBA (p=0.04), and rs13058338 in RAC2 (p=0.02) significantly increasing cardiotoxicity risk, while rs1045642 in ABCB1 and rs7853758 in SLC28A3 show cardioprotective properties.

A candidate gene association study in 100 Russian vitiligo patients and 100 controls identified a strong novel association between GSTP1 rs1138272 (Ala114Val, OR=13.03, Bonferroni-adjusted P=0.0015) and vitiligo susceptibility. Cumulative analysis of multiple xenobiotic metabolizing genes showed that carrying higher numbers of risk alleles was associated with increased vitiligo risk (9-16 vs 3-8 alleles: OR=2.79, P=0.00063), supporting a polygenic model for vitiligo involving detoxification pathway genes.

The Acute to Chronic Pain Signatures (A2CPS) is a multicenter prospective observational study protocol designed to identify biomarkers and biosignatures that predict development of chronic postsurgical pain. The study will recruit 3,600 patients undergoing knee arthroplasty or thoracic surgery and collect comprehensive biopsychosocial assessments including genetic variants via the Infinium Global Screening Array (GSA BeadChip with >650,000 markers), brain imaging, quantitative sensory testing, proteomic/metabolomic analyses, and patient-reported outcomes at baseline, 6 weeks, 3 months, and 6 months to identify predictive biomarkers for the transition from acute to chronic pain.

This retrospective cohort study of 187 Brazilian HIV patients examined associations between seven SNPs in five pharmacokinetic genes and virological failure on first-line protease inhibitor-based antiretroviral therapy. Two variants were significantly associated with treatment failure: rs1045642 (ABCB1) and rs212091 (ABCC1), suggesting that genetic variation in drug transporter proteins influences treatment outcomes in this population.

This study of 102 Mexican breast cancer patients undergoing FAC neoadjuvant chemotherapy found that ABCB1 rs1045642 (C3435T) polymorphism was significantly associated with chemotherapy response. Patients with C/C or C/T genotypes were more likely to be chemosensitive than T/T carriers (OR=4.055, p=0.0064). The C/C+C/T genotype was protective against chemoresistance in pathological response (OR=3.714, p=0.0104). ABCG2 rs2231142 (G421T) showed no significant association with chemotherapy response.

This case-control study of 283 SLE patients and 247 healthy controls in the Chinese Guangxi population found that MDR1 rs1128503 T allele and TT genotype were associated with increased systemic lupus erythematosus susceptibility (T allele: OR 1.36, 95% CI 1.07-1.74, P = 0.014; TT genotype: OR 1.77, 95% CI 1.08-2.88, P = 0.022), with stronger effects in older subjects (≥40 years). The rs1045642 polymorphism showed no significant associations with SLE risk.

Candidate gene association study of 67 genetic variants in 27 inflammation and DNA repair genes with hepatitis A virus (HAV) infection susceptibility in 6,779 NHANES III participants (2,619 non-Hispanic whites, 2,095 non-Hispanic blacks, 2,065 Mexican Americans). Among Mexican Americans, ABCB1 rs1045642 T allele was associated with lower HAV seropositivity risk (OR=0.79, p<0.001), while TGFB1 rs1800469 and XRCC1 rs1799782 T alleles were associated with increased risk (OR=1.38 and 1.57, respectively). CAT rs769214 and CYP2E1 rs2031920 showed marginal associations with decreased and increased HAV risk, respectively.

A candidate gene association study examining ABCB1 (MDR1) gene variants and corticosteroid dependence in 260 pediatric Crohn's disease patients. The rare C allele of rs2032583 conferred protection from corticosteroid dependency (OR=0.56, 95% CI: 0.34-0.95, P=0.029), with the heterozygous TC genotype also protective (OR=0.52, P=0.035). A three-marker haplotype was significantly associated with corticosteroid dependence after multiple comparison correction (P=0.004).

This pharmacogenetic study of 54 Asian nasopharyngeal cancer patients examined how polymorphisms in CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2, and SLCO1B3 affect docetaxel pharmacokinetics and toxicity. Patients homozygous for the variant allele (GG) of SLCO1B3 rs11045585 had significantly higher AUC and lower clearance of docetaxel (P = 0.026 and P = 0.036, respectively). ABCB1 heterozygotes showed the highest decrease in nadir hemoglobin (P = 0.006). The study suggests functional polymorphisms in SLCO1B3 and ABCB1 cooperatively influence docetaxel disposition.

This is a special issue of the Italian medical journal BeAdfiles (September 2012) dedicated to genetic conditioning in HIV and hepatitis virus infections. It reviews the major genetic polymorphisms that influence disease progression, treatment response, and drug toxicity in HIV and chronic hepatitis B and C infections, with particular emphasis on IL28B polymorphisms (rs809917 and others) predicting HCV treatment response to interferon-alpha and ribavirin therapy, and ITPA gene variants protecting against ribavirin-induced anemia. The issue also covers pharmacogenetic markers (CYP2B6, ABCB1, HLA-B*5701) and their clinical applications in antiretroviral therapy.

A population pharmacokinetics study of ciclosporin A (CsA) in 33 de novo kidney transplant recipients found that body weight explained 35% of variability in CsA clearance and prednisolone dose >20 mg/day explained 20% of within-patient variability. Genetic polymorphisms in ABCB1 (rs1128503, rs1045642, rs2032582), CYP3A4, CYP3A5, and PXR were not significantly associated with CsA pharmacokinetics after accounting for non-genetic covariates.

This systematic review of 98 studies examined biological predictors of clozapine response in treatment-resistant schizophrenia patients. Of 379 different gene variants investigated across 70 genetic studies, only three variants (DRD3 Ser9Gly rs6280, HTR2A His452Tyr, and GNB3 C825T) achieved independent replication. Non-genetic predictors included higher prefrontal cortical volumes and lower HVA:5-HIAA ratio in cerebrospinal fluid.

This case-control association study analyzed three ABCB1/MDR1 gene polymorphisms (rs1128503, rs2032582, rs1045642) in 95 Polish colorectal cancer patients to assess their role as prognostic factors. The T1236 allele (rs1128503) was significantly more frequent in early-stage tumors (T1/T2: 89.7%, M0: 81.6%, I/II: 82.7%) versus advanced-stage tumors (T3/T4: 68.2%, M1: 47.4%, III/IV: 65.1%, p=0.0021, HR=0.26, p=0.0424). The haplotype T1236-G2677-C3435 was detected only in less advanced tumors. Multivariate Cox regression identified T1236 allele as an independent protective prognostic factor for colorectal cancer survival.

This genome-wide association study identified the CYP2C19*2 loss-of-function variant (rs4244285) as a major determinant of clopidogrel response in 429 Amish individuals. The variant was associated with diminished platelet aggregation response to ADP stimulation (P=4.3×10⁻¹¹) and accounted for 12% of variation in clopidogrel response. In an independent cohort of 227 patients undergoing percutaneous coronary intervention, carriers of CYP2C19*2 had higher cardiovascular event rates (20.9% vs 10.0%, HR=2.42, P=.02).

A systematic review of 98 studies investigating biological predictors of clozapine response in treatment-resistant schizophrenia. Of 70 genetic studies examining 379 variants, only three genetic variants have independently replicated findings: DRD3 Ser9Gly (rs6280), HTR2A His452Tyr, and GNB3 C825T (rs5442/rs5443). Non-genetic predictors include higher prefrontal cortical structural integrity and activity, and lower HVA:5-HIAA ratio in cerebrospinal fluid.

This case-control study of 270 pediatric Crohn's disease cases and 336 controls examined 14 tag-SNPs in the ABCB1/MDR1 gene for associations with disease susceptibility and phenotypes. While SNP rs17327442 showed nominal association with overall CD susceptibility (OR=0.72, P=0.04), this did not withstand multiple testing correction. Two SNPs (rs10248420, rs2032583) were significantly associated with colonic disease location (L2±L4), and five SNPs were nominally associated with noninflammatory disease phenotype. Haplotype analysis revealed specific haplotypes associated with colonic and noninflammatory CD phenotypes.

Case-control study of 310 Croatian IBD patients (199 CD, 109 UC) and 120 healthy controls investigating MDR1 (ABCB1) polymorphisms C3435T (rs1045642) and G2677T (rs2032582). The 3435TT genotype was associated with UC (p=0.02; OR 2.12, 95% CI 1.11-4.03), and carriers of the 3435T/2677T haplotype had increased UC risk (p=0.02; OR 1.55, 95% CI 1.06-2.28). Heterozygous C3435T carriers showed protective effect in CD (p=0.02; OR 0.58).

This pharmacogenetics study analyzed 28 SNPs in methotrexate (MTX) metabolism genes (SLC19A1/RFC1, ABCB1, FPGS, GGH) in two Spanish populations with rheumatoid arthritis (n=124 and n=194). Key findings: FPGS rs10987742 and rs10106 associated with MTX response (p=0.033, p=0.041); FPGS rs10106 also associated with MTX survival (p=0.005) and toxicity (p=0.021); ABCB1 rs868755, rs10280623, rs1858923 associated with toxicity (p=0.025, p=0.048, p=0.031). In the first study, MTHFR rs17421511 (p=0.024) and rs1476413 (p=0.0086) associated with response, DHFR rs1643650 (p=0.026) associated with response, ATIC rs16853826 associated with toxicity (p=0.039).

This pharmacogenetic study examined genetic variants in the folate metabolism and MTX transport pathways in rheumatoid arthritis patients receiving methotrexate monotherapy. Study 1 (n=124) identified rs17421511 and rs1476413 in MTHFR and rs1643650 in DHFR as significantly associated with MTX treatment response (p=0.024, p=0.0086, p=0.026 respectively), and rs16853826 and rs10197559 in ATIC as associated with toxicity (p=0.039). Study 2 (n=194) found rs10106 and rs10987742 in FPGS associated with response, and rs868755, rs10280623, rs1858923 in ABCB1 associated with toxicity, with rs10106 also associated with longer MTX monotherapy survival.

A case-control study of 146 Bulgarian colorectal cancer patients and 160 healthy controls found no significant association between MDR1/ABCB1 polymorphisms 2677G>T (rs2032582) and 3435C>T (rs1045642) and sporadic colorectal cancer risk. The 2677T allele frequency was 43.5% in patients vs 44.1% in controls, and the 3435T allele frequency was 48.3% vs 50.9% (both P > 0.05). No differences were observed in haplotype frequencies or in tumor vs normal tissue genotypes.

This study characterized an Ashkenazi Jewish (AJ) population-specific genetic signature using genome-wide SNP data from 1,312 AJ individuals. Using ADMIXTURE and principal components analysis, the authors identified allelic patterns that differentiate AJ from European and Middle Eastern populations. Gene Ontology enrichment analysis of the AJ-specific genetic signature revealed enrichment in genes involved in transepithelial chloride transport (including CFTR with rs213950 showing V158M variant) and equilibrioception (PCDH15, CLRN1), implicating these pathways in the elevated prevalence of cystic fibrosis and Usher syndrome in Ashkenazi Jews. The study also identified disease-relevant alleles including MTHFR C677T (rs1801133), SH2B3 rs3184504 associated with type 1 diabetes/celiac disease, and MC1R rs1805005, and provided a validated set of 103 ancestry informative markers (AIMs) for population stratification correction.

A case-control study of 365 UC and 331 CD patients versus 550 controls in a Spanish population found that the PXR gene locus (specifically a risk haplotype rs3814055*T//rs6784598*C//rs2276707*C) was significantly associated with extensive ulcerative colitis (OR=1.66, 95% CI 1.20-2.30, P=0.001). The study also identified an epistatic interaction between PXR -25385C/T and MDR1 rs3789243, where carriers of risk alleles at both loci showed increased susceptibility to extensive UC.

A meta-analysis of 52 case-control studies (15,789 cases and 20,274 controls) examining associations between MDR1 (ABCB1) polymorphisms and cancer risk. The 3435C>T polymorphism showed significant association with cancer (OR=1.286, 95% CI=1.123-1.474 for TT vs CC), particularly in acute lymphoblastic leukemia (ALL: OR=1.890) and Caucasian populations. The 2677G>T/A polymorphism was associated with increased cancer risk overall (OR=1.348) and especially in Asian populations (OR=1.642). The 1236C>T polymorphism showed no significant association with cancer risk.

Population-based case-control study of 285 Russian colorectal cancer patients and 275 controls examining the association between MDR1/ABCB1 gene polymorphisms and cancer susceptibility. The study found a significant association between MDR1 genotypes (-129TT; 2677GG; 3435CC and -129TT; 2677TT; 3435TT) and colorectal cancer risk in lifelong non-smokers aged ≥63 years (OR=3.9, 95% CI: 2.0-7.7), with stronger effects for rectal cancer (OR=5.4) than colon cancer (OR=2.7). The association was dependent on smoking status and age, highlighting the interaction between genetic and lifestyle risk factors.